Drug resistance is a major impediment in cancer chemotherapy. Patients may acquire resistance during multiple cycles of therapy. Alternatively, patients may not respond at the onset of therapy (inherent resistance). Resistance to virtually all approved cancer cytotoxic chemotherapy has been reported including antimitic agents (paclitaxel and docetaxel, vinblastine, vincristine or vinorelbine), topoisomerase inhibitors (etoposide, teniposide, topotecan, camptothecin, doxorubicin and duanorubicin), antimetabolities (methotrexate, 5-fluorouracil, gemcitabine), alkylating agents (melphalan, chlorambucil), and other DNA damaging agents (cisplatin and its analogs). (Goldstein, L. J., Ozols, R. F. Anticancer Drug Resistance, p. 294. Boston: Kluwer Academic Publishers, 1994.) The mechanisms mediating resistance are highly diverse. Finding and developing chemical compounds having novel structures for use in tumor therapy and which overcome resistance is important.
Hemiasterlins are natural products derived from sponges that induce microtubule depolymerization, G2/M cell cycle arrest, and ultimately cell death.
Finding and developing chemical compounds having novel structures for use in tumor therapy and which overcome resistance is important. (Anderson, H. J., Coleman, J. E., Andersen, R. J., Roberge, M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation, Cancer Chemother. Pharmacol. 39: 223-226, 1997. Talpir, R., Benayahu, Y., Kashman, Y., Pannell, L., Schleyer, M. Hemiasterlin and geodiamolide TA: two new cytotoxic peptides from the marine sponge hemiasterella minor (kirkpatrick), Tetrahedron Letters 35: 4453-4456, 1994). Hemiasterlins in cancer therapy have been reported (WO 99/32509, WO 96/33211 and U.S. Pat. No. 6,153,590). Further, Hemiasterlin may be obtained from marine sponges (U.S. Pat. No. 5,661,175 (1997) and U.S. Pat. No. 6,153,590 (2000)) or synthesized (Andersen, R. J., Coleman, J. E. Tetrahedron Letters 38: 317-320, 1997). Synthetic analogs of hemiasterlin have also been prepared (WO 99/32509), and Hemiasterlin and the synthetic analogs thereof are reported to have cytotoxic and anti-mitotic activities.
The mechanisms that may mediate resistance to known antimitotic agents include drug efflux pumps (MDR1 and possibly MXR), tubulin mutations, alternative isotypes expression of tubulin isomers, alteration in the expression or function of genes that mediate apoptosis (e.g. p53 and bcl-2), and overexpression of growth factors such as HER-2. (Rowinsky, E. K., Tolcher, A. W. Antimicrotubule agents. In: J. Devita, V. T., Hellman, S., Rosenberg, S. A. (ed.) Cancer Principles and Practice, 6th edition, pp. 431-452. Philadelphia: Lippincott Williams and Wilkins, 2001) Resistance mediated by the multidrug drug resistance gene, MDR-1, has been intensively studied, mainly because it is frequently encountered in experimental models. (Greenberger, L. M., Cohen, D., and Horwitz, S. B. In vitro models of multiple drug resistance. In: a. R. F. O. L. J. Goldstein (ed.) Anticancer Drug Resistance, pp. 69-106. Norwell, M A: Kluwer Academic Publishers, 1994) MDR-1 is implicated in resistance to anti-microtubule agents since: 1) selection of tissue culture cells for resistance to vinca alkaloids or taxanes leads to marked overexpression of MDR-1, 2) cells that overexpress MDR-1 have low drug accumulation of taxanes or vinca alkaloids, 3) transfection of cells with MDR-1 induces resistance to these agents, 4) photoaffinity probes for vinca alkaloids or taxanes bind to the MDR-1 gene product, P-glycoprotein, 5) transgenic mice devoid of MDR gene family members have altered pharmacokinetic profiles for taxanes and 5) agents that inhibit P-glycoprotein resensitize resistant cells to taxanes or vinca alkaloids. The clinical relevance of MDR-1 overexpression is not clear in most solid tumor types and its association with lack of patient response or poor prognosis is controversial. (Bradshaw, D. M., Arceci, R. J. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance, J. Clin. Oncol. 16: 3674-3690, 1998) Nevertheless, overexpression of MDR1 has been clearly associated with response to chemotherapy and prognosis in leukemias. Low level resistance to vinca alkaloids (but not taxanes) has also been found in cells transfected with another efflux pump, MRP. (Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A., Kruh, G. D. Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution., Cancer Res. 55: 5342-5347, 1995; Zaman, G. J. R., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., and Borst, P. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump, Proc. Natl. Acad. Sci. USA. 91: 8822-8826,1994.)
Tubulin mutations have been found in cells selected for resistance to agents that polymerize microtubules, paclitaxel or epothilones. (Giannakakou, P., Gussio, R., Nogales, E., Downing, K. H., Zaharevitz, D., Bolbuck, B., Poy, G., Sackett, D., Nicolauo, K. C., Fojo, T. A common pharmacophore for epithilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells, Proc. Natl. Acad. Sci. USA. 97: 2904-2909, 2000; Giannakakou, P., Sackett, D. L., Kang, Y. -K., Zhan, A., Buters, J. T., M., Fojo, T., Poruchynsky, M. S. Paclitaxel-resistant human ovarian cancer cells have mutant b-tubulins that exhibit impaired paclitaxel-driven polymerization, J. Biol. Chem. 272: 17118-17125, 1997.) For paclitaxel resistance of this type, selection must be done with paclitaxel in the presence of an MDR-1 inhibitor to avoid the preferential overexpression of MDR1. Based on crystallographic data and molecular modeling of tubulin, the mutations occur in regions of tubulin thought to interact with taxanes. (Giannakakou, P., Gussio, R., Nogales, E., Downing, K. H., Zaharevitz, D., Bolbuck, B., Poy, G., Sackett, D., Nicolauo, K. C., Fojo, T. A common pharmacophore for epithilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells, Proc. Natl. Acad. Sci. USA. 97: 2904-2909, 2000.) While clinical significance is still being evaluated, one report found that 33% of patients with non-small cell carcinomas had tumors with tubulin mutations and such mutations are correlated with poor response to paclitaxel therapy. (Monzo, M., Rosell, R., Sanchez, J. J., Lee, J. S., O'Brate, A., Gonzalez-Larriba, J. L., Alberola, V., Lorenzo, J. C., Nunez, L., Ro, J. Y., Martin, C. Paclitaxel resistance in son-small cell lung cancer associated with beta-tubulin gene mutations, J. Clin. Oncol. 17: 1786—179, 1999.) Differential expression of tubulin isoforms has been found in some cell lines selected for paclitaxel or vinca alkaloid resistance. (Burkart, C. A., Kavallaris, M., Horwitz, S. B. The role of b-tubulin isotypes in resistance to antimitotic drugs, Biochim. Biophys. Acta. 1471: O1-9, 2001.) The clinical association with isotype alterations has not been fully studied, but alterations in isotype expression in patients resistant to paclitaxel have been found. (Kavallaris, M., Kuo, D. Y-. S., Burkhart, C. A., Regf, D. L., Norris, M. D., Haber, M., Horwitz, S. B. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific b-tubulin isotypes, J. Clin. Invest. 100: 1282-1293,1997.)
There is still a need for novel compounds which have chemical structures other than paclitaxel, which further have anticancer activity and in particular which have antimicrotubule activity against resistant cell lines and are useful for the treatment of cancer.